In the last few years there has been considerable interest among athletes in creatine, which occurs abundantly in skeletal muscle. Creatine plays a pivotal role in the regulation and homeostasis of skeletal muscle energy metabolism and it is now generally accepted that the maintenance of phospho-creatine availability is important to the continuation of muscle force production. Creatine may also be involved in other processes concerned with protein synthesis and hypertrophy of muscle fibers during training. Although creatine synthesis occurs in the liver, kidney and pancreas it has been known for sometime that the oral ingestion of creatine will add to the whole body creatine pool, and it has been shown that the ingestion of 20 to 30 g creatine monohydrate (Cr.H2O) per day for several days can lead to a greater than 20% increase in human skeletal muscle total creatine content. Thus, WO94/02127 discloses the administration of creatine monohydrate in amounts of at least 15 g (or 0.2–0.4 g/kg body weight) per day, for at least 2 days, for increasing muscular strength.
In fact, it was subsequently found that after several days of supplementation (20 g per day) with creatine monohydrate in order to attain initial elevation of the tissue stores, thereafter it takes no more than 2 to 3 g per day to maintain the newly elevated concentration. Supplementation with any bioavailable source of creatine (i.e. creatine supplementation) in an appropriate dose can provide improvements to athletes involved in explosive events, which include all events lasting from a few seconds to a few minutes (such as sprinting, swimming, weight-lifting etc). Endurance performance in events lasting longer than about 30 minutes appear less affected by creatine supplementation except where this involves short periods of increased energy output particularly when the local muscle carbohydrate stores have become depleted. Creatine is a normal food component and is not a drug and its use is not contrary to official regulations. It is possible that the greatest benefits of creatine supplementation are experienced by the elderly, vegetarians or those who eat no meat or fish, since these people tend to have low muscle creatine contents.
The inclusion of creatine in a drink would be highly desirable as a convenient means of providing creatine supplementation.
However, most drinks, especially fruit-flavored drinks, are acidic. It is well known that the creatine molecule is unstable in aqueous solutions at acid or neutral pH, and is converted into the related compound creatinine. This is highly significant as creatinine has no muscle performance-enhancing effect and is excreted from the human body as a waste product in urine. In view of the foregoing, EP 0 669 083 teaches that aqueous drinks for human consumption comprising creatine must be weakly alkaline, in order to limit the conversion of creatine into creatinine, and this has become the generally accepted opinion.
Furthermore, creatine and its derivatives have been used in the past but only for the preparation of products with a meaty or savory flavor. For instance, Tonsbeek (U.S. Pat. No. 3,615,600) discloses and is concerned with artificial flavoring, describing mixtures imparting a meaty flavor to foods. Similarly de Rooji (U.S. Pat. No. 4,464,409) is concerned with meat flavoring. Yamazaki (JP-A-59035663) prepares a meat flavor by heating a mixture comprising creatine at pH 5.0–7.0 at a temperature of 80–130° C. for 30–120 minutes. Under these conditions most of the creatine is converted to creatinine.
The inventors believe that it would not occur to the persons skilled in the art to add creatinine (used hitherto as a meat or savory flavoring agent) to compositions which were intended to have a flavor (especially a fruit flavor) other than meaty or savory. The person skilled in the art might have expected the addition of creatinine to result in an unpalatable combination of fruit and meat flavors, whereas in fact the inventors have found that the resulting combination does not impart an undesirable meaty flavor.
WO 97/45026 discloses an acidic composition for human consumption comprising creatine and its derivatives, the composition being provided as a dry powder or in liquid or semi-liquid form. The compositions disclosed therein are stable at refrigerated temperatures (4° C.) for prolonged periods but stable at ambient temperature for relatively short periods (e.g. up to, but not exceeding, 7 days).
WO 00/74500 discloses compositions comprising creatine and its derivatives suspended in aloe vera gel, which compositions were stable (with respect to the conversion of creatine to creatinine) at room temperature for 2 weeks or more, depending on the initial concentration of creatine in the composition.
Both WO 97/45026 and WO 00/74500 stress the desirability of preventing the conversion of creatine to creatinine, and neither document suggests the deliberate addition of creatinine to a creatine-containing composition intended for human consumption.
A very high proportion of the population consume drinks containing methyl xanthines. The methyl xanthines are a class of chemical compounds which include caffeine, theobromine, and theophylline. These are present in coffee, tea and cocoa. The major methyl xanthine in coffee is caffeine, in tea caffeine and theophylline and in cocoa caffeine and theobromine.
The methyl xanthines have desirable pharmacological effects. They act as stimulants, are anti-soporific, elevate mood, decrease fatigue, and increase the capacity to work.
The most studied methyl xanthine is caffeine. Caffeine is particularly useful to athletes and sports people. Graham (Sports Medicine 31, 787, 2001) after a study of the literature concluded that caffeine enables athletes to train at a greater power, with greater speed and for longer time. Thus, it increases power, speed and endurance in simulated and actual race conditions. It is also useful as an anti-soporific for young people who for social reasons wish to go to bed late and for people such as drivers who must stay awake. Caffeine also stimulates the metabolic rate and it is used in a number of preparations for weight reduction.
Because of these above-mentioned pharmacological properties, caffeine is an important ingredient in soft drinks such as the colas to which it is added on as a pure substance or as Guarana extract (Guarana is a plant indigenous to the Amazon basin which contains abundant caffeine and related alkaloids) or cola extract. One drink which has become extremely popular especially among young people is Red BullR™ which in addition to caffeine contains taurine (which is a non-protein amino-acid occurring in high levels in the brain, retina and muscle tissue including heart muscle) and vitamins.
The half life of ingested caffeine in the human body is 5–6 hours which means that after one day there are only small quantities left in the circulation.
It is not obvious for those skilled in the art to formulate a drink which comprises each of creatine, creatinine and methyl xanthine.
Firstly, in order to obtain physiological value from a creatine drink containing, for example, a typical dose of 2–3 gms creatine, it requires several weeks' consumption of the drink: one drink has no significant effect. Over several weeks the creatine will accumulate in muscle as phosphocreatine and be available for energy production. In contrast, the opposite is true of caffeine- or other methyl xanthine-based drinks: the physiological effect from just one drink is immediate. Thus, creatine and methyl xanthines have very different pharmacokinetic profiles in the body.
Secondly, Vandeberg et al, (1996 J. Appl. Physiology 80, 452–457) found that caffeine counteracted the ergogenic action of muscle creatine loading, such that the two substances were antagonistic.